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Hypoxia inhibits HUNK-mediated phosphorylation of GEF-H1 for epithelial-to-mesenchymal transition

ABSTRACT: Hypoxia regulates epithelial to mesenchymal transition (EMT) of cancer cells. However, the mechanism underlying hypoxia-mediated EMT remains largely unknow. Here, utilizing colorectal cell carcinoma (CRC) as a model, we find that HUNK inhibits EMT and suppresses metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at ser645 site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Moreover, hypoxia suppresses HUNK activity and dephosphorylates GEF-H1 to promote EMT. Clinically, the expression levels of both HUNK and phosphorylation of GEH-H1 ser645 are not only downregulated in CRC tissues with metastasis compared to that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of hypoxia-regulated HUNK kinase activity and phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE203440 | GEO | 2022/05/27

REPOSITORIES: GEO

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Project description:Accumulating evidence suggests that epithelial-mesenchymal transition (EMT) contributes to metastasis, a major cause of death in patients with colorectal cancer (CRC). MeCP2 (methyl CpG binding protein 2), a key modulator for initiating gene transcription, plays a pivotal role in EMT, but its upstream signaling pathways are poorly understood. We collected 137 colorectal cancer patients’ samples, including tumor tissues (n=137), adjacent normal tissues (n=137) and liver metastases (n=11). Three pairs of colorectal cancer cell lines were sequenced to identify high abundance of lincRNAs in primary tumor tissues. Two independent experiments (electrophoretic mobility shift assay and RNA immunoprecipitation assay) were used to characterize the interaction between LINC00261 and MeCP2. Subsequently, the effects of LINC00261 on phosphorylation of MeCP2 and promotion of the MeCP2-ZEB1 feedback were examined. Consequently long intergenic non-protein coding RNA 261 (LINC00261) was down-regulated in highly metastatic CRC cells and liver metastases from patients with CRC. Down-regulating LINC00261 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple CRC cell lines. Furthermore, knocking down LINC00261 increased colon-derived liver metastasis in an orthotopic CRC model and promoted distant metastatic colonization in a lung metastasis model. Mechanistic studies revealed that LINC00261 interacted with MeCP2 and stabilized it in the nucleus by inhibiting Ser80 phosphorylation Interestingly, ZEB1 could re-modulate MeCP2 expression by binding to the MeCP2 promoter, and they formed a positive feedback loop consequently. In contrast, the lower LINC00261 expression in CRC samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. Taken together, LINC00261 suppresses EMT and CRC cells’ metastatic potential by negatively regulating the MeCP2-ZEB1 feedback loop; LINC00261’s loss in metastatic tissues may be a potential prognostic marker of aggressive disease.